Process for the production of 2H-cyclopenta (b) furan-2-one compounds

ABSTRACT

The present invention concerns a novel process for preparing derivatives useful in the production of prostaglandins. 
     The present invention provides a process for the production of a compound of formula I ##STR1## wherein R 1  is a protecting group which comprises hydrolyzing a compound of formula II ##STR2## wherein R 1  is as defined above and R 2  is a leaving group, under acidic conditions.

The present invention concerns a novel process for preparing derivativesuseful in the production of prostaglandins.

The present invention provides a process for the production of acompound of formula I ##STR3## wherein R₁ is a protecting group whichcomprises hydrolysing a compound of formula II ##STR4## wherein R₁ is asdefined above and

R₂ is a leaving group, under acidic conditions.

The reaction is effected in the presence of an aqueous acid, usingconditions such that the group R₁ is not split off. The group R₁ is thusan acid stable group, but as will be appreciated from the preferredpreparation of the compound of formula II as described hereinafter R₁ isalso preferably a group inert under oxidation conditions, and from thepreferred use of the compound of formula I as described hereinafter R₁may also be capable of being selectively split off in the presence of anester group. A suitable group is benzyl which may be substituted in thephenyl ring with at least one inert substituent.

R₂ is a group capable of leaving under aqueous acidic conditions, e.g.acetoxy or preferably chloro or bromo.

The reaction is conveniently effected in the presence of a strong acid,e.g. a strong organic acid, such as p-toluene sulphonic acid, orpreferably a mineral acid such as HCl or HBr.

The reaction medium is conveniently more acidic than pH 2. Preferablythe pH is from 0.5 to 2, e.g. 1 to 2.

The reaction temperature is conveniently from 0° to 90° C. It is to beappreciated that when high temperatures are used, e.g. from 50° to 90°C, weaker acidic conditions can be tolerated than at low temperatures,e.g. 0° to 20° C, thereby minimising side reactions.

It is preferred to use a inert water-miscible organic solvent such asacetone, tetrahydrofuran or dioxane.

The resultant compound of formula I may be isolated and purified inconventional manner.

A compound of formula II may be obtained in conventional manner byoxidising a compound of formula III ##STR5## wherein R₁ and R₂ aredefined above e.g. using m-chloroperbenzoic acid.

A compound of formula III may be obtained in conventional manner byreacting a compound of formula IV ##STR6## wherein R₁ is as defined inclaim 1 with a compound of formula R₂ H wherein R₂ is as defined above.

A compound of formula IV may be obtained by oxidising a compound offormula V ##STR7## wherein R₁ is as defined above in conventionalmanner, e.g. with chromium trioxide in acetone.

A compound of formula V may be obtained by selectively protecting thehydroxy methyl group in the known compound of formula VI ##STR8##

It is to be appreciated that in a compound of formula V or VI thehydroxy group may be in the α or β position. Alternatively a compound offormula V or VI may be used as a mixture of the α and β-isomers.

Insofar as the production of any starting material is not particularlydescribed, this may be produced and purified in analogous manner toknown processes or to processes described herein.

As already indicated, the compounds of formula I are known usefulintermediates for the production of prostaglandins and intermediatestherefor. For example a compound of formula I may be acylated with anacid halide to yield the known compounds of formula VII, ##STR9##wherein R₁ is as defined above, e.g. benzyl, and

R₃ CO is acyl, e.g. pC₆ H₅.C₆ H₄.CO.

The compound of formula VII may be selectively deprotected to producethe known compounds of formula VIII ##STR10## wherein R₃.CO is asdefined above.

Processes for the production for the compounds of formulae VII and VIIIusing a compound of formulae II, III, IV or V are novel and form part ofthe invention. Compounds of formulae II, III, IV and V are also noveland also form part of the invention.

In the following Examples all temperatures are uncorrected.

EXAMPLEr-4-benzyloxymethyl-3,t-3a,4,5,6,t-6a-hexahydro-t-5-hydroxy-2H-cyclopenta[b]furan-2-one[compound of formula I]

A mixture consisting of 11.5 g of8-anti-benzyloxymethyl-6-exo-chloro-2-oxabicyclo[3.2.1]octan-3-one, 90ml of actone, 30 ml of water and 6 ml of 10% hydrochloric acid is heatedto reflux for 15 hours. The acetone is removed in a vacuum and 27 ml of10% caustic soda is added to the residue, a two-phase mixture, and thisis stirred for two hours at room temperature. It is then acidified (pH =2) with 1,5 ml of concentrated hydrochloric acid, and the aqueous phaseis extracted in three portions with chloroform. The combined chloroformextracts are washed once with saturated sodium bicarbonate solution,dried over sodium sulphate and evaporated in a vacuum to give the titlecompound.

The 8-anti-benzyloxymethyl-6-exo-chloro-2-oxabicyclo [3.2.1]octan-3-oneused as the starting compound is produced as follows:

(A) 7-anti-benzyloxymethyl-tricyclo[2.2.1.0²,6 ]heptan-3-α and β-ol

8.0 g of a mixture of 3α and 3β-hydroxy-tricyclo [2.2.1.0²,6]heptan-7-anti-methanol which has been dissolved in 10 ml oftetrahydrofuran are added in drops in a nitrogen atmosphere at areaction temperature of 60° C to a suspension of 6.12 g of sodiumhydride in 125 ml of toluene. The reaction temperature is then increasedto 85° C, and 31.6 g of benzyl chloride, dissolved in 50 ml of toluene,together with 17 g of a mixture of 3α- and 3β-hydroxytricyclo[2.2.1.0²,6] heptan-7-anti-methanol, dissolved in 20 ml of tetrahydrofuran, areadded simultaneously over the course of 15 minutes. After this addition,the mixture is stirred for another 45 minutes at 85° C, and then 85 mlof 3% ammonium chloride solution are added with cooling by ice. Afterseparating the aqueous phase, the organic phase is washed with 10%tartaric acid solution, dried over sodium sulphate and compressed in avacuum. The residue, a bright oil, is subjected to distillation. The7-anti-benzyloxymethyltricyclo[2.2.1.0²,6 ]heptan-3α and β-ol mixture isdistilled over at a boiling point of 120°-122° C (0.02 mm) as acolourless, slightly viscose oil.

(B) 7-anti-benzyloxymethyl-tricyclo[2.2.1.0²,6 ]heptan 3-one

2.76 g of chormium trioxide and 2.25 ml of concentrated sulphuric acid,dissolved in 10 ml of water, are added in drops with ice cooling overthe course of 30 minutes to a solution of 9.6 g of7-anti-benzyloxymethyl-tricyclo[2.2.1.0²,6 ]heptan-3α and β-ol mixturein 150 ml of actone. This is subsequently stirred for 30 minutes, theactone is removed in a vacuum, and the concentrate is extracted withtoluene in two portions. The toluene phase is washed with saturatedsodium bicarbonate solution, dried over sodium sulphate and compressedin a vacuum until dry. The yellow oil which is produced in purified bychromatography on silica gel and the pure7-anti-benzyloxymethyl-tricyclo [2.2.1.0²,6 ]heptan-3-one is thusobtained.

(C) 7-anti-benzyloxymethyl-5-exo-chlorobicyclo[2.2.1]heptan-3-one

50 g of 7-anti-benzyloxymethyl-tricyclo[2.2.1.0²,6 ]heptan-3-one aredissolved with ice cooling in 750 ml of ethanolic hydrochloric acid (33%g/g) and are stirred for 4.5 hours at an internal temperature of 4° C.150 ml of water are added in drops over the course of 15 minutes,whereby the temperature increases to 20° C. The reaction mixture is thenconcentrated in a vacuum and the evaporation residue is absorbed in 400ml of water and 500 ml of toluene. After vigorous shaking, the aqueousphase is separated and the organic phase is washed successively with 300ml of water, 300 ml of saturated sodium bicarbonate solution and 600 mlof water. After drying over sodium sulphate, the toluene phase isconcentrated in a vacuum and the residue, a slightly yellow oil, issubjected to distillation. The7-anti-benzyloxymethyl-5-exo-chloro-bicyclo[2.2.1]heptan-3-one isdistilled over at a boiling point of 145°-146° C (0.02 mm).

(D) 8-anti-benzyloxymethyl-6-exo-chloro-2-oxabicyclo[3.2.1]octan-3-one

A solution of 53.6 g of m-chloroperbenzoic acid in 530 ml of methylenechloride is added in drops over the course of one hour at 20°-22° C(water bath cooling) to a mixture consisting of 56.0 g ofanti-benzyloxymethyl-5-exo-chlorobicyclo[2.2.1]heptan-3-one, 23.3 g ofsodium bicarbonate and 850 ml of methylene chloride. The reactionmixture is subsequently stirred at room temperature for four hours. Itis then cooled by an ice bath and after stirring for half an hour, it isfiltered. 200 ml of 7% caustic soda are added to the filtrate with icecooling. The organic phase is separated and is washed successively with400 ml of water, 300 ml of 10% sodium bisulphite solution, 200 ml ofsaturated sodium bicarbonate solution and finally 400ml of water. Themethylene chloride phase thus treated is dried over sodium sulphate andcompletely concentrated in a vacuum. This produces a bright yellow oil,consisting of 8-anti-benzyloxy-methyl-6-exo-chloro-2-oxabicyclo[3.2.1.]octan-3-one.

I claim:
 1. A process for the production of a compound of formula I##STR11## wherein R₁ is a protecting group which comprises hydrolysing acompound of formula II ##STR12## wherein R₁ is as defined above, and R₂is a leaving group under acidic conditions at a pH which is more acidicthan pH₂.
 2. A process according to claim 1 effected at a pH of from 0.5to
 2. 3. A process according to claim 1, wherein the compound of formulaII is obtained by oxidising a compound of formula III, ##STR13## whereinR₁ and R₂ are as defined in claim
 1. 4. A process according to claim 3wherein the compound of formula III is obtained by reacting a compoundof formula IV ##STR14## wherein R₁ is as defined in claim 4, with acompound HR₂ wherein R₂ is as defined in claim
 1. 5. A process accordingto claim 1 wherein R₂ is chlorine or bromine.
 6. A process according toclaim 4, wherein the compound of formula IV is obtained by oxidising acompound of formula V ##STR15## wherein R₁ is as defined in claim
 5. 7.A process according to claim 1 wherein R₁ is benzyl.
 8. A processaccording to claim 6, wherein a compound of formula V is obtainedselectively protecting the hydroxymethyl group in a compound of formulaVI, ##STR16##